Integrated receiver for continuous analyte sensor

ABSTRACT

A system is provided for monitoring glucose in a host, including a continuous glucose sensor that produces a data stream indicative of a host&#39;s glucose concentration and an integrated receiver that receives the data stream from the continuous glucose sensor and calibrates the data stream using a single point glucose monitor that is integral with the integrated receiver. The integrated receiver obtains a glucose value from the single point glucose monitor, calibrates the sensor data stream received from the continuous glucose sensor, and displays one or both of the single point glucose measurement values and the calibrated continuous glucose sensor values on the user interface.

RELATED APPLICATION

This application is a division of U.S. application Ser. No. 10/991,966,filed Nov. 17, 2004, which claims the benefit of priority under 35U.S.C. § 119(e) to U.S. Provisional Application No. 60/523,840, filedNov. 19, 2003, U.S. Provisional Application 60/587,787, filed Jul. 13,2004, and U.S. Provisional Application No. 60/614,683, filed Sep. 30,2004, each of which is incorporated by reference herein in its entirety,and each of which is hereby made a part of this specification.

FIELD OF THE INVENTION

The present invention relates generally to systems and methods formonitoring glucose in a host. Particularly, a device for continuousglucose sensing is provided with an integrated receiver for single pointglucose measurement and subsequent calibration of the continuous glucosesensor within the device.

BACKGROUND OF THE INVENTION

A variety of continual and continuous glucose sensors have beendeveloped for detecting and/or quantifying analytes in a biologicalfluid sample, for example, glucose sensors that continually orcontinuously measure glucose concentration in a host. Typically, theseglucose sensors require a reference glucose measurement with which tocalibrate the sensor-measured glucose values. Additionally, long-termimplantable glucose sensors typically request regular updates ofcalibration, for example new reference glucose values every day, week,or month. Accordingly, a user has typically been required to keep trackof and even stay close to (for example, carry) a device associated withthe continuous glucose sensor that receives and processes data from thecontinuous glucose sensor. Additionally, a user has typically beenrequired to carry a separate device that provides a reference glucosevalue for calibration of the continuous glucose sensor. Many timesadditional hardware, such as cables, test strips, and other auxiliarydevices are necessary to connect, test, and otherwise use the devices.Therefore, the use of a continuous device can be cumbersome,particularly when the user is away from home.

Furthermore, continuous sensors have conventionally been calibratedusing a reference glucose monitor that uses different measurementtechnology than that of the continuous sensor, which can increase theerror within the calibrated sensor values. For example, an implantableglucose sensor that contains a membrane containing glucose oxidase istypically calibrated using self-monitoring blood glucose (SMBG) teststrip-based measurement values. Unfortunately, such SMBG tests have anerror of ±20% and additionally cannot be calibrated by the user.Furthermore, because the reference measurement device (for example,SMBG) is independent from the continuous glucose sensor, the possibilityof accuracy in reporting time of SMGB can be prone to human error.

SUMMARY OF THE INVENTION

A continuous glucose sensor that includes simpler or fewer componentsthan prior art sensors, that is user friendly, that exhibits reducederror within the calibrated sensor values, and/or is less prone to humanerror is desirable.

Accordingly, in a first embodiment, a device for monitoring glucoseconcentration in a biological sample of a host is provided, the devicecomprising a continuous glucose sensor that produces a data streamindicative of a host's glucose concentration; an integrated receiverthat receives the data stream from the continuous glucose sensor,wherein the integrated receiver comprises a microprocessor comprisingprogramming to process the data stream received from glucose sensor; anda single point glucose monitor adapted to receive a biological samplefrom the host and measure the concentration of glucose in the sample;wherein the microprocessor further comprises programming to calibratethe data stream using the glucose concentration measured by the singlepoint glucose monitor.

In an aspect of the first embodiment, the continuous glucose sensorcomprises a sensing membrane comprising an enzyme; and anelectrochemical cell that measures the glucose concentration.

In an aspect of the first embodiment, the single point glucose monitorcomprises a sensing membrane comprising an enzyme; and anelectrochemical cell that measures a concentration of glucose in thesample.

In an aspect of the first embodiment, the integrated receiver furthercomprises a user interface for displaying glucose concentration datafrom at least one of the continuous glucose sensor and the single pointglucose monitor.

In a second embodiment, a method for calibrating a continuous glucosesensor in an integrated receiver is provided, the method comprisingcontinually receiving a data stream in the integrated receiver from acontinuous glucose sensor; measuring a glucose concentration of abiological sample using a single point glucose monitor integral with theintegrated receiver; and calibrating the data stream within theintegrated receiver using the glucose concentration measured by thesingle point glucose monitor.

In an aspect of the second embodiment, the method further comprises thestep of displaying the glucose concentration measured by the singlepoint glucose monitor.

In an aspect of the second embodiment, the method further comprises thestep of displaying a calibrated data stream.

In a third embodiment, a device for calibrating continuous glucosesensor data is provided, the device comprising a single point glucosemonitor adapted to measure a glucose concentration in a biologicalsample; a receiver for receiving a data stream from a continuous glucosesensor; a microprocessor comprising programming to calibrate the datastream from the continuous glucose sensor using the glucoseconcentration measured from the single point glucose monitor.

In an aspect of the third embodiment, the continuous glucose sensorcomprises a sensing membrane comprising an enzyme; and anelectrochemical cell that measures the glucose concentration.

In an aspect of the third embodiment, the single point glucose monitorcomprises a sensing membrane comprising an enzyme; and anelectrochemical cell that measures the glucose concentration in thebiological sample.

In an aspect of the third embodiment, the device further comprises auser interface adapted to display glucose data from at least one of thecontinuous glucose sensor and the single point glucose monitor.

In an aspect of the third embodiment, the glucose monitor comprises asensing region comprising a sensing membrane and at least twoelectrodes, wherein the sensing region is located within the integratedreceiver.

In an aspect of the third embodiment, the integrated receiver comprisesa removable cartridge, and wherein the sensing region is located withinthe removable cartridge.

In an aspect of the third embodiment, the integrated receiver comprisesa housing, and wherein the glucose monitor comprises a sensing regionmovably mounted to the integrated receiver housing.

In an aspect of the third embodiment, the device further comprises astylus movably mounted to the integrated receiver housing, and whereinthe sensing region is located on the stylus.

In an aspect of the third embodiment, the device further comprises areceiving chamber located within the integrated receiver housing, andwherein the stylus is received within the receiving chamber for storage.

In an aspect of the third embodiment, the device further comprises asterile solution chamber located at an end of the receiving chamber suchthat the sensing region is operably associated with the sterile solutionchamber when the stylus is received within the receiving chamber forstorage.

In an aspect of the third embodiment, the device further comprises asterile solution port configured for refilling the sterile solutionchamber with a sterile solution.

In an aspect of the third embodiment, the device further comprises adispensing chamber located in the integrated receiver housing, thedispensing chamber adapted to dispense at least one disposablebioprotective film onto the sensing region.

In an aspect of the third embodiment, the device further comprises astorage chamber located in the integrated receiver housing, the storagechamber adapted to store the disposable bioprotective film.

In an aspect of the third embodiment, the device further comprises ashuttle mechanism located on the integrated receiver housing, theshuttle mechanism adapted to load the disposable bioprotective film intothe dispensing chamber.

In an aspect of the third embodiment, the device further comprises atleast one bioprotective film that is adapted to stretch or stick ontothe sensing region to protect the sensing region from damage, clogging,or contamination from a biological fluid.

In an aspect of the third embodiment, the bioprotective film furthercomprises a sensing membrane comprising an enzyme.

In an aspect of the third embodiment, the sensing region comprises asensing membrane and at least two electrodes, wherein the sensingmembrane is disposed over the electrodes adapted for measuring a glucoseconcentration in a biological sample.

In an aspect of the third embodiment, the single point glucose monitorcomprises a sensor port that houses a sensing region adapted formeasuring a glucose concentration in the biological sample.

In an aspect of the third embodiment, the device further comprises adisposable capillary tube, wherein the capillary tube is configured tocreate a capillary action capable of drawing a liquid biological samplefrom a first end of the tube to a second end of the tube.

In an aspect of the third embodiment, the capillary tube comprises afilter configured to permit passage of glucose, but to filter or blockpassage of an undesired species or a contaminating species in thebiological sample.

In an aspect of the third embodiment, the capillary tube furthercomprises a vent configured to allow displaced air within the capillarytube to escape therefrom.

In an aspect of the third embodiment, n the sensor port comprises acover adapted for protecting the sensing region.

In an aspect of the third embodiment, the disposable capillary tubecomprises a sensing membrane, wherein the sensing membrane comprises aresistance domain, an enzyme domain, an interference domain, and anelectrolyte domain.

In an aspect of the third embodiment, the single point glucose monitorand the receiver are detachably connected to each other.

In an aspect of the third embodiment, the single point glucose monitorand the receiver each comprise at least one contact adapted for operableconnection when detachably connected to each other.

In an aspect of the third embodiment, the microprocessor is locatedwithin the receiver.

In an aspect of the third embodiment, the device further comprises amicroprocessor located within the single point glucose monitor, whereinthe microprocessor is adapted for communication between the single pointglucose monitor and the receiver when the single point glucose monitorcontact and the receiver contact are operably connected.

In a fourth embodiment, a device for monitoring a glucose concentrationin a biological sample in a host is provided, the device comprising acontinuous glucose sensor configured to produce a data stream indicativeof a glucose concentration in a biological sample of a host, wherein theglucose sensor comprises a sensing membrane comprising a catalyst,wherein the membrane is operably associated with at least two electrodesthat are operably connected to an electrical circuit adapted forcontinuous glucose sensing; a single point glucose monitor configured toproduce a glucose concentration measurement from a biological sampleobtained from a host, wherein the glucose monitor comprises a sensingmembrane comprising a catalyst, wherein the membrane is operablyassociated with at least two electrodes that are operably connected toan electrical circuit adapted for measuring the glucose concentration inthe biological sample; a receiver integral with the single point glucosemonitor adapted to receive a data stream from the continuous glucosesensor; and a microprocessor integral with the single point glucosemonitor that comprises programming to calibrate the data stream from thecontinuous glucose sensor using the glucose concentration measurementfrom the single point glucose monitor.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram that illustrates an integrated receiver in oneembodiment in wireless communication with a continuous glucose sensor.

FIG. 2A is an exploded perspective view of one exemplary embodiment of acontinuous glucose sensor.

FIG. 2B is an expanded view of an alternative exemplary embodiment of acontinuous glucose sensor, illustrating the in vivo portion of thesensor.

FIG. 3 is a block diagram that illustrates the continuous glucose sensorelectronics in one embodiment.

FIG. 4A is a perspective view of an integrated receiver in oneembodiment showing a single point glucose monitor in its closedposition.

FIG. 4B is an exploded perspective view of the integrated receiver ofFIG. 4A showing the single point glucose monitor with a cover removed.

FIG. 5A is a perspective view of an integrated receiver housing inanother embodiment, showing a single point glucose monitor including astylus movably mounted to the integrated receiver, wherein the stylus isshown in a storage position.

FIG. 5B is a perspective view of the integrated housing of FIG. 5A,showing the stylus in a testing position.

FIG. 5C is a perspective view of a portion of the stylus of FIG. 5A,showing the sensing region.

FIG. 5D is a perspective view of the integrated receiver housing of FIG.5A, showing the stylus loaded with a disposable film, and in its testingposition.

FIG. 5E is a perspective view of a portion of the stylus of FIG. 5A,showing the sensing region with a disposable film stretched and/ordisposed thereon for receiving a biological sample.

FIG. 6A is a perspective view of an integrated receiver in yet anotherembodiment, including a single point glucose monitor and a disposablecapillary tube for transferring a biological sample to a sensing regionon the monitor.

FIG. 6B is a perspective view of the integrated receiver of FIG. 6A,showing the disposable capillary tube inserted into the single pointglucose monitor to transfer the biological sample to a sensing region onthe single point glucose monitor.

FIG. 6C is an expanded perspective view of a portion of the integratedreceiver of FIG. 6A, showing the capillary tube inserted into the singlepoint glucose monitor.

FIG. 6D is a schematic cross-sectional view of a capillary tube and aportion of the integrated receiver of FIG. 6A, illustrating thecapillary tube in contact with the sensing membrane such that glucosefrom the biological sample can be measured by electrodes on the sensingregion.

FIG. 6E is a schematic cross-sectional view of the capillary tube ofFIG. 6A, illustrating an embodiment wherein a filter is located on oneend.

FIG. 6F is a schematic cross-sectional view of the capillary tube ofFIG. 6A, illustrating an embodiment wherein a filter is disposed withina wall of the capillary tube.

FIG. 6G is a schematic cross-sectional view of the capillary tube ofFIG. 6A, illustrating an embodiment wherein a vent extends from thecapillary tube.

FIG. 6H is a schematic illustration of one embodiment, wherein thecapillary tube is round in shape with an inner capillary tube that isalso round in shape.

FIG. 6I is a schematic illustration of one embodiment, wherein thecapillary tube is rectangular in shape with an inner capillary tube thatis formed therein.

FIG. 6J is a schematic illustration of one embodiment, wherein thecapillary tube is rectangular in shape an inner capillary tube has arounded structure.

FIG. 7A is a perspective view of an integrated receiver in yet anotherembodiment, wherein the single point glucose monitor is detachablyconnected to the receiver to form a modular configuration, shown in itsattached state.

FIG. 7B is a perspective view of the integrated receiver of FIG. 7A,shown in its detached state.

FIG. 8 is a block diagram that illustrates integrated receiverelectronics in one embodiment.

FIG. 9 is a flow chart that illustrates the process of initialcalibration of the continuous glucose sensor and data output of theintegrated receiver in one embodiment.

FIG. 10 is a graph that illustrates one exemplary embodiment of aregression performed on a calibration set to create a conversionfunction.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The following description and examples illustrate some exemplaryembodiments of the disclosed invention in detail. Those of skill in theart will recognize that there are numerous variations and modificationsof this invention that are encompassed by its scope. Accordingly, thedescription of a certain exemplary embodiment should not be deemed tolimit the scope of the present invention.

Definitions

In order to facilitate an understanding of the preferred embodiments, anumber of terms are defined below.

The term “continuous glucose sensor,” as used herein, is a broad termand are used in its ordinary sense, including, without limitation, adevice that continuously or continually measures glucose concentration,for example, at time intervals ranging from fractions of a second up to,for example, 1, 2, or 5 minutes, or longer. It should be understood thatcontinuous glucose sensors can continually or continuously measureglucose concentration without requiring user initiation and/orinteraction for each measurement, such as described with reference toU.S. Pat. No. 6,001,067, for example.

The phrase “continuous glucose sensing,” as used herein, is a broad termand is used in its ordinary sense, including, without limitation, theperiod in which monitoring of plasma glucose concentration iscontinuously or continually performed, for example, at time intervalsranging from fractions of a second up to, for example, 1, 2, or 5minutes, or longer.

The term “single point glucose monitor,” as used herein, is a broad termand is used in its ordinary sense, including, without limitation, adevice that can be used to measure a glucose concentration within a hostat a single point in time, for example, some embodiments utilize a smallvolume in vitro glucose monitor that includes an enzyme membrane such asdescribed with reference to U.S. Pat. No. 4,994,167 and U.S. Pat. No.4,757,022. It should be understood that single point glucose monitorscan measure multiple samples (for example, blood or interstitial fluid);however only one sample is measured at a time and typically requiressome user initiation and/or interaction.

The term “capillary action,” as used herein, is a broad term and is usedin its ordinary sense, including, without limitation, the phenomenon ofa liquid, such as water or blood, spontaneously creeping up a thin tubeor fiber due to adhesive or cohesive forces or surface tension.

The term “biological sample,” as used herein, is a broad term and isused in its ordinary sense, including, without limitation, sample of ahost body, for example blood, interstitial fluid, spinal fluid, saliva,urine, tears, sweat, or the like.

The term “host,” as used herein, is a broad term and is used in itsordinary sense, including, without limitation, mammals such as humans.

The term “biointerface membrane,” as used herein, is a broad term and isused in its ordinary sense, including, without limitation, a permeableor semi-permeable membrane that can include two or more domains and istypically constructed of materials of a few microns thickness or more,which can be placed over the sensing region to keep host cells (forexample, macrophages) from gaining proximity to, and thereby damagingthe sensing membrane or forming a barrier cell layer and interferingwith the transport of glucose across the tissue-device interface.

The term “sensing membrane,” as used herein, is a broad term and is usedin its ordinary sense, including, without limitation, a permeable orsemi-permeable membrane that can be comprised of two or more domains andis typically constructed of materials of a few microns thickness ormore, which are permeable to oxygen and are optionally permeable toglucose. In one example, the sensing membrane comprises an immobilizedglucose oxidase enzyme, which enables an electrochemical reaction tooccur to measure a concentration of glucose.

The term “domain,” as used herein is a broad term and is used in itsordinary sense, including, without limitation, regions of a membranethat can be layers, uniform or non-uniform gradients (for example,anisotropic), functional aspects of a material, or provided as portionsof the membrane.

As used herein, the term “copolymer,” as used herein, is a broad termand is used in its ordinary sense, including, without limitation,polymers having two or more different repeat units and includescopolymers, terpolymers, tetrapolymers, etc.

The term “sensing region,” as used herein, is a broad term and is usedin its ordinary sense, including, without limitation, the region of amonitoring device responsible for the detection of glucose. In oneembodiment, the sensing region generally comprises a non-conductivebody, a working electrode (anode), a reference electrode and a counterelectrode (cathode) passing through and secured within the body formingan electrochemically reactive surface at one location on the body and anelectronic connection at another location on the body, and a sensingmembrane affixed to the body and covering the electrochemically reactivesurface. During general operation of the sensor a biological sample (forexample, blood or interstitial fluid) or a portion thereof contacts (forexample, directly or after passage through one or more domains of thesensing membrane) an enzyme (for example, glucose oxidase); the reactionof the biological sample (or portion thereof) results in the formationof reaction products that allow a determination of the glucose level inthe biological sample.

The term “electrochemically reactive surface,” as used herein, is abroad term and is used in its ordinary sense, including, withoutlimitation, the surface of an electrode where an electrochemicalreaction takes place. In the case of an electrochemical glucose sensor,hydrogen peroxide produced by an enzyme catalyzed reaction of theglucose being detected reacts at a working electrode creating ameasurable electronic current (for example, detection of glucoseutilizing glucose oxidase produces H₂O₂ as a by product, H₂O₂ reactswith the surface of the working electrode producing two protons (2H⁺),two electrons (2e⁻) and one molecule of oxygen (O₂) which produces theelectronic current being detected). In the case of the counterelectrode, a reducible species (for example, O₂) is reduced at theelectrode surface in order to balance the current being generated by theworking electrode.

The term “electrochemical cell,” as used herein, is a broad term and isused in its ordinary sense, including, without limitation, a device inwhich chemical energy is converted to electrical energy. Such a celltypically consists of two or more electrodes held apart from each otherand in contact with an electrolyte solution. Connection of theelectrodes to a source of direct electric current renders one of themnegatively charged and the other positively charged. Positive ions inthe electrolyte migrate to the negative electrode (cathode) and therecombine with one or more electrons, losing part or all of their chargeand becoming new ions having lower charge or neutral atoms or molecules;at the same time, negative ions migrate to the positive electrode(anode) and transfer one or more electrons to it, also becoming new ionsor neutral particles. The overall effect of the two processes is thetransfer of electrons from the negative ions to the positive ions, achemical reaction.

The term “proximal” as used herein, is a broad term and is used in itsordinary sense, including, without limitation, near to a point ofreference such as an origin or a point of attachment. For example, insome embodiments of a sensing membrane that covers an electrochemicallyreactive surface, the electrolyte domain is located more proximal to theelectrochemically reactive surface than the interference domain.

The term “distal” as used herein, is a broad term and is used in itsordinary sense, including, without limitation, spaced relatively farfrom a point of reference, such as an origin or a point of attachment.For example, in some embodiments of a sensing membrane that covers anelectrochemically reactive surface, a resistance domain is located moredistal to the electrochemically reactive surfaces than the enzymedomain.

The term “substantially” as used herein, is a broad term and is used inits ordinary sense, including, without limitation, being largely but notnecessarily wholly that which is specified.

The terms “microprocessor” and “processor,” as used herein, are broadterms and are used in their ordinary sense, including, withoutlimitation, a computer system or state machine designed to performarithmetic and logic operations using logic circuitry that responds toand processes the basic instructions that drive a computer.

The term “EEPROM,” as used herein, is a broad term and is used in itsordinary sense, including, without limitation, electrically erasableprogrammable read-only memory, which is user-modifiable read-only memory(ROM) that can be erased and reprogrammed (for example, written to)repeatedly through the application of higher than normal electricalvoltage.

The term “SRAM,” as used herein, is a broad term and is used in itsordinary sense, including, without limitation, static random accessmemory (RAM) that retains data bits in its memory as long as power isbeing supplied.

The term “A/D Converter,” as used herein, is a broad term and is used inits ordinary sense, including, without limitation, hardware and/orsoftware that converts analog electrical signals into correspondingdigital signals.

The term “RF transceiver,” as used herein, is a broad term and is usedin its ordinary sense, including, without limitation, a radio frequencytransmitter and/or receiver for transmitting and/or receiving signals.

The terms “raw data stream” and “data stream,” as used herein, are broadterms and are used in their ordinary sense, including, withoutlimitation, an analog or digital signal directly related to the measuredglucose from the glucose sensor. In one example, the raw data stream isdigital data in “counts” converted by an A/D converter from an analogsignal (for example, voltage or amps) representative of a glucoseconcentration. The terms broadly encompass a plurality of time spaceddata points from a substantially continuous glucose sensor, whichcomprises individual measurements taken at time intervals ranging fromfractions of a second up to, for example, 1, 2, or 5 minutes or longer.

The term “counts,” as used herein, is a broad term and is used in itsordinary sense, including, without limitation, a unit of measurement ofa digital signal. In one example, a raw data stream measured in countsis directly related to a voltage (for example, converted by an A/Dconverter), which is directly related to current from the workingelectrode. In another example, counter electrode voltage measured incounts is directly related to a voltage.

The term “electronic circuitry,” as used herein, is a broad term and isused in its ordinary sense, including, without limitation, thecomponents (for example, hardware and/or software) of a deviceconfigured to process data. In the case of a glucose-measuring device,the data includes biological information obtained by a sensor regardinga particular glucose in a biological fluid, thereby providing dataregarding the amount of that glucose in the fluid. U.S. Pat. Nos.4,757,022, 5,497,772 and 4,787,398, which are hereby incorporated byreference, describe suitable electronic circuits that can be utilizedwith devices of the preferred embodiments.

The term “potentiostat,” as used herein, is a broad term and is used inits ordinary sense, including, but not limited to, an electrical systemthat applies a potential between the working and reference electrodes ofa two- or three-electrode cell at a preset value and measures thecurrent flow through the working electrode. The potentiostat forceswhatever current is necessary to flow between the working and reference(2 electrode) or counter (3 electrode) electrodes to keep the desiredpotential, as long as the needed cell voltage and current do not exceedthe compliance limits of the potentiostat.

The term “electrical potential,” as used herein, is a broad term and isused in its ordinary sense, including, without limitation, theelectrical potential difference between two points in a circuit which isthe cause of the flow of a current.

The terms “operably connected” and “operably linked,” as used herein,are broad terms and are used in their ordinary sense, including, withoutlimitation, one or more components being linked to another component(s)in a manner that allows transmission of signals between the components.For example, one or more electrodes can be used to detect the amount ofglucose in a sample and convert that information into a signal. Thesignal can then be transmitted to an electronic circuit. In this case,the electrode is “operably linked” to the electronic circuit. Theseterms are broad enough to include wireless connectivity.

The term “linear regression,” as used herein, is a broad term and isused in its ordinary sense, including, without limitation, finding aline in which a set of data has a minimal measurement from that line.Byproducts of this algorithm include a slope, a y-intercept, and anR-Squared value that determine how well the measurement data fits theline.

The term “non-linear regression,” as used herein, is a broad term and isused in its ordinary sense, including, without limitation, fitting a setof data to describe the relationship between a response variable and oneor more explanatory variables in a non-linear fashion.

Overview

FIG. 1 is a perspective view of a device in one embodiment including acontinuous glucose sensor and an integrated receiver that has a singlepoint glucose monitor thereon. The continuous glucose sensor 10continuously measures glucose concentration in a host to provide a datastream representative of the host's glucose concentration, such asdescribed in more detail below with reference to FIGS. 2 and 3. Ingeneral, the integrated receiver 12 includes a single point glucosemonitor 14, electronic circuitry that processes data from the continuousglucose sensor 10 and the single point glucose monitor 14, and a userinterface 16 that displays glucose data to a user, all of which aredescribed in more detail with reference to FIGS. 4 to 10. Wirelesstransmissions 18 allow communication between the glucose sensor 10 andthe integrated receiver 12, for example, so that the integrated receiver12 can receive a data stream from the continuous glucose sensor 10.

Continuous Glucose Sensor

The preferred embodiments provide a continuous glucose sensor thatmeasures a concentration of glucose or a substance indicative of theconcentration or presence of the glucose. In some embodiments, theglucose sensor is an invasive, minimally-invasive, or non-invasivedevice, for example a subcutaneous, transdermal, or intravasculardevice. In some embodiments, the device can analyze a plurality ofintermittent biological samples. The glucose sensor can use any methodof glucose-measurement, including enzymatic, chemical, physical,electrochemical, spectrophotometric, polarimetric, calorimetric,radiometric, or the like. In alternative embodiments, the sensor can beany sensor capable of determining the level of an analyte in the body,for example oxygen, lactase, hormones, cholesterol, medicaments,viruses, or the like.

The glucose sensor uses any known method to provide an output signalindicative of the concentration of the glucose. The output signal istypically a raw data stream that is used to provide a useful value ofthe measured glucose concentration to a patient or doctor, for example.

One exemplary embodiment is described in detail below, which utilizes animplantable glucose sensor. However, it should be understood that thedevices and methods described herein can be applied to any devicecapable of continually or continuously detecting a concentration ofanalyte of interest and providing an output signal that represents theconcentration of that analyte.

FIG. 2A is an exploded perspective view of one exemplary embodiment of acontinuous glucose sensor 10 a. In this embodiment, the sensor ispreferably wholly implanted into the subcutaneous tissue of a host, suchas described in co-pending patent application Ser. No. 10/885,476 filedJul. 6, 2004 and entitled “SYSTEMS AND METHODS FOR MANUFACTURE OF ANANALYTE-MEASURING DEVICE INCLUDING A MEMBRANE SYSTEM”; co-pending U.S.patent application Ser. No. 10/838,912 filed May 3, 2004 and entitled,“IMPLANTABLE ANALYTE SENSOR”; U.S. patent application Ser. No.10/789,359 filed Feb. 26, 2004 and entitled, “INTEGRATED DELIVERY DEVICEFOR A CONTINUOUS GLUCOSE SENSOR”; U.S. application Ser. No. 10/646,333filed Aug. 22, 2003 entitled, “OPTIMIZED SENSOR GEOMETRY FOR ANIMPLANTABLE GLUCOSE SENSOR”; U.S. application Ser. No. 10/633,367 filedAug. 1, 2003 entitled, “SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSORDATA”; and U.S. Pat. No. 6,001,067 issued Dec. 14, 1999 and entitled“DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS”, each of which areincorporated herein by reference in their entirety. In this exemplaryembodiment, a body 20 and a sensing region 21 house the electrodes 22and sensor electronics (FIG. 3). The three electrodes 22 are operablyconnected to the sensor electronics (FIG. 3) and are covered by asensing membrane 23 and a biointerface membrane 24, which are attachedby a clip 25.

In one embodiment, the three electrodes 22 include a platinum workingelectrode, a platinum counter electrode, and a silver/silver chloridereference electrode. The top ends of the electrodes are in contact withan electrolyte phase (not shown), which is a free-flowing fluid phasedisposed between the sensing membrane 23 and the electrodes 22. Thesensing membrane 23 includes an enzyme, for example, glucose oxidase,and covers the electrolyte phase. The biointerface membrane 24 coversthe sensing membrane 23 and serves, at least in part, to protect thesensor 10 a from external forces that can result in environmental stresscracking of the sensing membrane 23. Copending U.S. patent applicationSer. No. 10/647,065, entitled, “POROUS MEMBRANES FOR USE WITHIMPLANTABLE DEVICES,” describes a biointerface membrane that can be usedin conjunction with the preferred embodiments, and is incorporatedherein by reference in its entirety.

In one embodiment, the biointerface membrane 24 generally includes acell disruptive domain most distal from the electrochemically reactivesurfaces and a cell impermeable domain less distal from theelectrochemically reactive surfaces than the cell disruptive domain. Thecell disruptive domain is preferably designed to support tissueingrowth, disrupt contractile forces typically found in a foreign bodyresponse, encourage vascularity within the membrane, and disrupt theformation of a barrier cell layer. The cell impermeable domain ispreferably resistant to cellular attachment, impermeable to cells, andcomposed of a biostable material.

In one embodiment, the sensing membrane 23 generally provides one ormore of the following functions: 1) protection of the exposed electrodesurface from the biological environment, 2) diffusion resistance(limitation) of the analyte, 3) a catalyst for enabling an enzymaticreaction, 4) limitation or blocking of interfering species, and 5)hydrophilicity at the electrochemically reactive surfaces of the sensorinterface, such as described in co-pending U.S. patent application Ser.No. 10/838,912, filed May 3, 2004 and entitled “IMPLANTABLE ANALYTESENSOR,” which is incorporated herein by reference in its entirety.Accordingly, the sensing membrane 23 preferably includes a plurality ofdomains or layers, for example, an electrolyte domain, an interferencedomain, an enzyme domain (for example, glucose oxidase), a resistancedomain, and can additionally include an oxygen domain (not shown),and/or a bioprotective domain (not shown), such as described in moredetail in the above-cited U.S. patent application Ser. No. 10/838,912.However, it is understood that a sensing membrane modified for otherdevices, for example, by including fewer or additional domains is withinthe scope of the preferred embodiments.

In some embodiments, the domains of the biointerface and sensingmembranes are formed from materials such as silicone,polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene,polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene,homopolymers, copolymers, terpolymers of polyurethanes, polypropylene(PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF),polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA),polyether ether ketone (PEEK), polyurethanes, cellulosic polymers,polysulfones and block copolymers thereof including, for example,di-block, tri-block, alternating, random and graft copolymers.Co-pending U.S. patent application Ser. No. 10/838,912, which isincorporated herein by reference in its entirety, describes biointerfaceand sensing membrane configurations and materials that can be applied tothe preferred embodiments.

In the illustrated embodiment, the counter electrode is provided tobalance the current generated by the species being measured at theworking electrode. In the case of a glucose oxidase based glucosesensor, the species being measured at the working electrode is H₂O₂.Glucose oxidase catalyzes the conversion of oxygen and glucose tohydrogen peroxide and gluconate according to the following reaction:

Glucose+O₂→Gluconate+H₂O₂

The change in H₂O₂ can be monitored to determine glucose concentrationbecause for each glucose molecule metabolized, there is a proportionalchange in the product H₂O₂. Oxidation of H₂O₂ by the working electrodeis balanced by reduction of ambient oxygen, enzyme generated H₂O₂, orother reducible species at the counter electrode. The H₂O₂ produced fromthe glucose oxidase reaction further reacts at the surface of workingelectrode and produces two protons (2H⁺), two electrons (2e⁻), and oneoxygen molecule (O₂).

In one embodiment, a potentiostat is employed to monitor theelectrochemical reaction at the electrochemical cell. The potentiostatapplies a constant potential to the working and reference electrodes todetermine a current value. The current that is produced at the workingelectrode (and flows through the circuitry to the counter electrode) issubstantially proportional to the amount of H₂O₂ that diffuses to theworking electrode. Accordingly, a raw signal can be produced that isrepresentative of the concentration of glucose in the user's body, andtherefore can be utilized to estimate a meaningful glucose value, suchas described herein.

FIG. 2B is an expanded view of an alternative exemplary embodiment of acontinuous glucose sensor, illustrating the in vivo portion of thesensor. Co-pending U.S. Provisional Application 60/587,787, filed Jul.13, 2004 and U.S. Provisional Application 60/614,683, filed Sep. 30,2004, describe systems and methods suitable for the transcutaneoussensor of the illustrated embodiment; however, one skilled in the artappreciates a variety of transcutaneous sensors that can benefit fromthe integrated receiver of the preferred embodiments.

In this embodiment, the in vivo portion of the sensor 10 b is theportion adapted for insertion under the host's skin, while an ex vivoportion of the sensor 10 b is the portion that remains above the host'sskin after sensor insertion and operably connects to an electronics unit(not shown). The sensor 10 b two or more electrodes: a working electrode26 and at least one additional electrode 28, which can function as acounter and/or reference electrode, hereinafter referred to as thereference electrode. Each electrode is formed from a fine wire, with adiameter in the range of 0.001 to 0.010 inches, for example, and can beformed from plated wire or bulk material.

In one embodiment, the working electrode 26 comprises a wire formed froma conductive material, such as platinum, palladium, graphite, gold,carbon, conductive polymer, or the like. The working electrode 26 isconfigured and arranged to measure the concentration of an analyte. Theworking electrode 20 is covered with an insulating material, for examplea non-conductive polymer. Dip-coating, spray-coating, or other coatingor deposition techniques can be used to deposit the insulating materialon the working electrode, for example. In one preferred embodiment, theinsulating material comprises Parylene, which can be an advantageousconformal coating for its strength, lubricity, and electrical insulationproperties, however, a variety of other insulating materials can beused, for example, fluorinated polymers, polyethyleneterephthalate,polyurethane, polyimide, or the like.

The reference electrode 28, which can function as a reference electrodealone, or as a dual reference and counter electrode, is formed fromsilver, Silver/Silver chloride, or the like. In one embodiment, thereference electrode 28 is formed from a flat wire with rounded edges inorder to decrease sharp edges and increase host comfort. Preferably, thereference electrode 28 is juxtapositioned and/or twisted with or aroundthe working electrode 26; however other configurations are alsopossible. In some embodiments, the reference electrode 28 is helicallywound around the working electrode 26 (see FIG. 2B). The assembly ofwires is then optionally coated together with an insulating material,similar to that described above, in order to provide an insulatingattachment. Some portion of the coated assembly structure is thenstripped, for example using an excimer laser, chemical etching, or thelike, to expose the necessary electroactive surfaces. In oneimplementation, a window 28 is formed on the insulating material toexpose an electroactive surface of the working electrode and at leastsome edges of the sensor are stripped to expose sections ofelectroactive surface on the reference electrode. Other methods andconfigurations for exposing electroactive surfaces are also possible,for example by exposing the surfaces of the working electrode 26 betweenthe coils of the reference electrode 28. In some alternativeembodiments, additional electrodes can be included within the assembly,for example, a three-electrode system (working, reference, and counterelectrodes) and/or including an additional working electrode (which canbe used to generate oxygen, configured as a baseline subtractingelectrode, or configured for measuring additional analytes, forexample).

A sensing membrane (not shown) is deposited over the electroactivesurfaces of the sensor 10 b (working electrode and optionally referenceelectrode) and includes a plurality of domains or layers, such asdescribed above, with reference to FIG. 2A. The sensing membrane can bedeposited on the exposed electroactive surfaces using known thin filmtechniques (for example, spraying, electro-depositing, dipping, or thelike). In one exemplary embodiment, each domain is deposited by dippingthe sensor into a solution and drawing out the sensor at a speed thatprovides the appropriate domain thickness. In general, the membranesystem can be disposed over (deposited on) the electroactive surfacesusing methods appreciated by one skilled in the art.

In the illustrated embodiment, the sensor glucose oxidaseelectrochemical sensor, wherein the working electrode 26 measures thehydrogen peroxide produced by an enzyme catalyzed reaction of theanalyte being detected and creates a measurable electronic current (forexample, detection of glucose utilizing glucose oxidase produces H₂O₂peroxide as a by product, H₂O₂ reacts with the surface of the workingelectrode producing two protons (2H⁺), two electrons (2e⁻) and onemolecule of oxygen (O₂) which produces the electronic current beingdetected), such as described in more detail above and as is appreciatedby one skilled in the art.

FIG. 3 is a block diagram that illustrates the continuous glucose sensorelectronics in one embodiment. In this embodiment, a potentiostat 30 isshown, which is operably connected to electrodes 24 a (FIG. 2) or 24 b(FIG. 3) to obtain a current value, and includes a resistor (not shown)that translates the current into voltage. An A/D converter 32 digitizesthe analog signal into “counts” for processing. Accordingly, theresulting raw data stream in counts is directly related to the currentmeasured by the potentiostat 30.

A microprocessor 34 is the central control unit that houses EEPROM 36and SRAM 38, and controls the processing of the sensor electronics.Certain alternative embodiments can utilize a computer system other thana microprocessor to process data as described herein. In otheralternative embodiments, an application-specific integrated circuit(ASIC) can be used for some or all the sensor's central processing. TheEEPROM 36 provides semi-permanent storage of data, for example, storingdata such as sensor identifier (ID) and programming to process datastreams (for example, programming for data smoothing and/or replacementof signal artifacts such as described in copending U.S. patentapplication entitled, “SYSTEMS AND METHODS FOR REPLACING SIGNALARTIFACTS IN A GLUCOSE SENSOR DATA STREAM,” filed Aug. 22, 2003). TheSRAM 38 can be used for the system's cache memory, for example fortemporarily storing recent sensor data. In some alternative embodiments,memory storage components comparable to EEPROM and SRAM can be usedinstead of or in addition to the preferred hardware, such as dynamicRAM, non-static RAM, rewritable ROMs, flash memory, or the like.

A battery 40 is operably connected to the microprocessor 34 and providesthe necessary power for the sensor 10. In one embodiment, the battery isa Lithium Manganese Dioxide battery, however any appropriately sized andpowered battery can be used (for example, AAA, Nickel-cadmium,Zinc-carbon, Alkaline, Lithium, Nickel-metal hydride, Lithium-ion,Zinc-air, Zinc-mercury oxide, Silver-zinc, and/or hermetically-sealed).In some embodiments the battery is rechargeable. In some embodiments, aplurality of batteries can be used to power the system. A Quartz Crystal42 is operably connected to the microprocessor 34 and maintains systemtime for the computer system as a whole.

An RF Transceiver 44 is operably connected to the microprocessor 34 andtransmits the sensor data from the sensor 10 to a receiver (see FIGS. 4to 8) within a wireless transmission 46 via antenna 48. Although an RFtransceiver is shown here, some other embodiments can include a wiredrather than wireless connection to the receiver. In yet otherembodiments, the receiver can be transcutaneously powered via aninductive coupling, for example. A second quartz crystal 50 provides thesystem time for synchronizing the data transmissions from the RFtransceiver. The transceiver 44 can be substituted with a transmitter inother embodiments. In some alternative embodiments other mechanisms suchas optical, infrared radiation (IR), ultrasonic, or the like can be usedto transmit and/or receive data.

In one alternative embodiment, the continuous glucose sensor comprises atranscutaneous sensor such as described in U.S. Pat. No. 6,565,509 toSay et al. In another alternative embodiment, the continuous glucosesensor comprises a subcutaneous sensor such as described with referenceto U.S. Pat. No. 6,579,690 to Bonnecaze et al. or U.S. Pat. No.6,484,046 to Say et al. In another alternative embodiment, thecontinuous glucose sensor comprises a refillable subcutaneous sensorsuch as described with reference to U.S. Pat. No. 6,512,939 to Colvin etal. In another alternative embodiment, the continuous glucose sensorcomprises an intravascular sensor such as described with reference toU.S. Pat. No. 6,477,395 to Schulman et al. In another alternativeembodiment, the continuous glucose sensor comprises an intravascularsensor such as described with reference to U.S. Pat. No. 6,424,847 toMastrototaro et al. All of the above patents are incorporated in theirentirety herein by reference.

Although a few exemplary embodiments of continuous glucose sensors areillustrated and described herein, it should be understood that thedisclosed embodiments are applicable to a variety of continuous glucosesensor configurations.

Integrated Receiver

The integrated receiver provides an integrated housing that includes asingle point glucose monitor, electronics (for example, hardware andsoftware) useful to receive and process data from the continuous glucosesensor and the single point glucose monitor, and a user interface thatdisplays processed data to a user (for example, patient or doctor).FIGS. 4 to 7 illustrate preferred embodiments of the integrated receiverwith a single point glucose monitor. FIGS. 8 to 10 illustrate somepreferred electronics and data processing within the integrated receiverthat are applicable to all embodiments of the integrated receiver (forexample, FIGS. 4 to 7). Because the single point glucose monitor isintegrated into the continuous sensor's receiver housing, there is noneed for a separate glucose monitor to provide reference values forcalibration or the like.

In the illustrated embodiments, the single point glucose monitorincludes a meter for measuring glucose within a biological sampleincluding a sensing region that has a sensing membrane impregnated withan enzyme, similar to the sensing membrane described with reference toFIG. 2, and such as described with reference to FIGS. 4 to 7. However,in alternative embodiments, the single point glucose monitor can useother measurement techniques such as optical, for example.

FIG. 4A is a perspective view of an integrated receiver in oneembodiment showing a single point glucose monitor in its closedposition. FIG. 4B is an exploded perspective view of the integratedreceiver, showing the single point glucose monitor with the coverremoved to reveal the receptacle inside. The integrated receiver 12provides a housing that integrates a single point glucose monitor 14 andelectronics (FIG. 8) useful to receive, process and display data on theuser interface 16. The single point glucose monitor permits rapid andaccurate measurement of the amount of a particular substance (forexample, glucose) in a biological fluid.

The integrated receiver 12 includes a main housing 62 and a cartridge 64that is removably mounted on the housing 62, which permits the cartridge64 to be disposable and replaceable as needed. The housing 62 includes acase 66 having an upper portion 68 and a lower portion 70. The upperportion 68 and lower portion 70 are connected together by any particularfastening means such as several screws (not shown).

The main housing 62 also includes electronic circuitry operablyconnected to at least two electrodes (not shown). The electrodes arepreferably mounted within a sensing region 72 that supports theelectrodes as they extend upwardly therein. A sensing membrane (notshown) overlays the electrodes on the sensing region 72 and is operablyassociated with the electrodes when the cartridge is removably mountedon the housing. The cartridge 64 also includes means for protecting thesensing membrane when not in use. The protection means is preferably acover 74 that is movably mounted on a body portion 76 of the cartridge64. Alternatively, the cover 74 can be mounted on the case 66. In theillustrated embodiment, a hinge assembly 78 movably mounts the cover 74on the body portion 76.

Generally, the cover 74 has a first position such as shown in FIG. 4A inwhich it protects the membrane, and a second position. Access to thesensing membrane is preferable in order to conveniently place thebiological fluid sample on the sensing membrane for analysis.

The housing 62 preferably defines a well 80 having a bottom 82. Inpractice, the biological fluid sample is placed on the sensing region 72in the well 80 for analysis. Generally, the well 80 defines an openingof less than 4 millimeters in diameter and less than 2 millimeters indepth. As a result, the well has a volume of less than about 0.1 to 0.2cubic centimeters. These dimensions substantially minimize the size ofthe biological fluid sample necessary for analysis down to the samplesizes as small as about five microliters. Because the size of the samplecan be particularly small, compensation for temperature changes duringanalysis that was often necessary with previous devices can be avoided.

The protection means of the cartridge 64 preferably also includes meansfor sealing the well 80 and hence the sensing region including thesensing membrane, which is disposed at the bottom of the well 80, fromthe ambient surroundings.

A retaining means is also provided for releasably retaining thecartridge 64 and its body portion 76 on the housing 62. The retainingmeans preferably includes a detent 84 on the cartridge 64, which isreceived in a recess defined by the upper portion 68 of the case 66. Theretaining means also preferably includes at least one, preferably twowings 86 on the body portion 76 of the cartridge 64 which are receivedin one or more slots 88 on the case 66. The slots 88 are generallyperpendicular to the cover 74 so that opening the cover will notdisengage the wings 86 from the slots 88.

The sensing region 72, in which the electrodes are disposed, ispreferably generally annular in design with the interior portion thereoffilled with an electrically nonconductive support material such as ahardened polyepoxide-containing resin. The electrically nonconductivesupport material and the top (electrochemically reactive) surfaces ofthe electrodes define a sensing membrane contact surface. Namely, thesensing membrane can be stretched over the contact surface to moreeffectively place the membrane in operative association with theelectrodes (not shown). In an alternative embodiment of the sensingregion 72, the electrodes can be deposited onto a ceramic surface, andan electrically nonconductive material can be applied as a coating overthe electrodes to form an insulating barrier. A portion of eachelectrode, however, is not coated to form a membrane contact surface sothat a membrane can be applied over the electrodes in operative contacttherewith.

Generally, the sensing membrane can be constructed substantially similarto the sensing membrane described with reference to FIG. 2. For example,the sensing membrane includes a resistance domain most distal from theelectrochemically reactive surfaces, an enzyme domain less distal fromthe electrochemically reactive surfaces than the resistance domain, aninterference domain less distal from the electrochemically reactivesurfaces than the enzyme domain, and an electrolyte domain adjacent tothe electrochemically reactive surfaces. However, it is understood thatthe sensing membrane can be modified for other devices, for example, byincluding fewer or additional domains. Furthermore, designconsiderations for the sensing membrane of the single point glucosemonitor can differ from that of the continuous glucose sensor due tooxygen availability, for example.

In some embodiments, the domains of the sensing membrane are formed frommaterials such as silicone, polytetrafluoroethylene,polyethylene-co-tetrafluoroethylene, polyolefin, polyester,polycarbonate, biostable polytetrafluoroethylene, homopolymers,copolymers, terpolymers of polyurethanes, polypropylene (PP),polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutyleneterephthalate (PBT), polymethylmethacrylate (PMMA), polyether etherketone (PEEK), polyurethanes, cellulosic polymers, polysulfones andblock copolymers thereof including, for example, di-block, tri-block,alternating, random and graft copolymers.

The cover 74 is preferably provided with a closure means (not shown)such as one or more latches that engage the body portion 76. Generally,the force necessary to disengage the closure means from the body portionshould be less than that necessary to disengage the wings 86 from theslots 88. In this manner, an operator can easily open the cover 74without accidentally disengaging the cartridge 64 from the main housing62.

The sensing region 72, including the electrodes and sensing membrane,contacts the body fluid sample for analysis. The sensing region 72 isoperably associated with the electronic circuitry (see FIG. 8) thatanalyzes the current from the reaction of the components in the bodyfluid with the electrodes. The electronic circuitry is in turn operablyassociated with the user interface 16 (for example, such as a liquidcrystal display) to indicate glucose concentration.

In one embodiment, the electrode configuration includes athree-electrode electrochemical cell, which in combination with thechemical reactions occurring in the sensing membrane and on theelectrochemically reactive surfaces, makes possible consistent electrodebehavior and, in particular, performance of a reference electrode thatis stable with time. However, in alternative embodiments, wherein theelectrode configuration includes a two-electrode electrochemical cellwith a reference cathodic, chloride ions will be lost from the referenceelectrode that eventually leads to unstable electrode behavior.According to the preferred embodiments, permanent stable referenceelectrode behavior is achieved when the hydrogen peroxide produced inthe membrane oxidizes the silver metal to silver oxide which is thenconverted to silver chloride by chloride ion. Advantages include ease ofmanufacturing of the electrode, self-forming and self-maintainingelectrode behavior, and long-term reference electrode stability.

In general, the glucose measurement technique of the integrated receiver12 is similar to that described with reference to FIGS. 2 and 3, above,however the electronics are adapted for single point measurement. Theelectronics associated with the integrated receiver 12 are described inmore detail below with reference to FIG. 8. Generally, glucose from abiological sample produces a current flow at a working electrode, withequal current provided by a counter electrode in a reference circuit.The current is converted in an analog section by a current to voltageconverter to a voltage, which is inverted, level-shifted, and deliveredto an A/D converter in the microprocessor (see FIG. 8). As part of thecalibration, the microprocessor can set the analog gain via its controlport. The A/D converter is preferably activated at one-second intervals.The microprocessor looks at the converter output with any number ofpattern recognition algorithms known to those skilled in the art until aglucose peak is identified. A timer is then activated for about 30seconds at the end of which time the difference between the first andlast electrode current values is calculated. This difference is thendivided by the value stored in the memory during instrument calibrationand is then multiplied by the calibration glucose concentration. Theresult includes a calibrated glucose concentration value that ismeaningful to a user, and useful in calibrating the data stream from thecontinuous glucose sensor 10, for example.

The single point glucose monitor described with reference to FIGS. 4Aand 4B can be calibrated by the user as described in more detail withreference to U.S. Pat. Nos. 4,994,167 and 4,757,022, both of which areincorporated herein in their entirety. The ability to calibrate theglucose monitor is particularly advantageous, for example, as comparedto a conventional test strip, which cannot be calibrated by the user.

Additionally, the similarity of the sensing membranes used for thecontinuous glucose sensor and the single point glucose sensor providesan internal control that creates increased reliability by nature ofconsistency and decreased error potential that can otherwise beincreased due to combining dissimilar measurement techniques.Additionally, the disclosed membrane system is known to providelongevity, repeatability, and cost effectiveness, for example ascompared to single use strips, or the like.

During the data processing, prompts or messages can be displayed on theuser interface 16 to guide the user through the calibration and samplemeasurement procedures. In addition, prompts can be displayed to informthe user about necessary maintenance procedures, such as “ReplaceSensor” or “Replace Battery.” An on/off button 90 preferably initiatesthe operation and calibration sequences.

Methods and devices that can be suitable for use in conjunction withaspects of the above-described preferred embodiments are disclosed incopending applications including U.S. Pat. No. 4,994,167 and U.S. Pat.No. 4,757,022. The integrated receiver electronics and its integrationwith the continuous glucose sensor are described in more detail belowwith reference to FIGS. 8 to 10.

FIGS. 5A to 5E illustrate another embodiment of an integrated receiver,wherein the single point glucose monitor includes a stylus movablymounted to the integrated receiver for measurement of glucose in abiological sample. FIG. 5A is a perspective view of the integratedreceiver housing in another embodiment, showing a single point glucosemonitor including a stylus movably mounted to the integrated receiver,wherein the stylus is shown in a storage position. FIG. 5B is aperspective view of the integrated housing of FIG. 5A, showing thestylus in a testing position. FIG. 5C is a perspective view of a portionof the stylus of FIG. 5A, showing the sensing region. FIG. 5D is aperspective view of the integrated receiver housing of FIG. 5A, showingthe stylus loaded with a disposable film, and in its testing position.FIG. 5E is a perspective view of a portion of the stylus of FIG. 5A,showing the sensing region with a disposable film stretched and/ordisposed thereon.

In this embodiment, the integrated receiver provides 92 a housing thatintegrates a single point glucose monitor 94 and electronics (see FIG.8) useful to receive, process, and display data on the user interface96. The single point glucose monitor 94 permits rapid and accuratemeasurement of the amount of a particular substance (for example,glucose) in a biological fluid. Generally, the integrated receiverelectronics process single point glucose monitor data, receive andprocess continuous glucose sensor data, including calibration of thecontinuous sensor data using the single point monitor data for example,and output data via the user interface 96, such as is described below inmore detail with reference to FIG. 8.

The single point glucose monitor 94 includes a stylus 98 that is movablymounted to the integrated receiver housing 92 via a connector 93. Theconnector 93 can be a cord, bar, hinge, or any such connection meansthat allows the stylus to move from a first (storage) position (FIG. 5A)to a second (testing) position (FIG. 5B) on the housing. The stylus isnot constrained to the first and second positions; rather the stylus canbe configured to swing at various angles, about various pivots, or inany manner allowed by the connector for convenience to the user. In somealternative embodiments, the stylus 98 is removably mounted on theintegrated receiver housing 92 and an operable connection can beestablished using a wireless connection, or alternatively usingelectrical contacts that operably connect the stylus 98 that isremovably mounted onto the integrated receiver housing 92.

The stylus 98 includes a sensing region 100 on one end that is operablyconnected to the integrated receiver's electronics (FIG. 8). As bestillustrated in FIG. 5C, the sensing region 100 is provided with at leasttwo, preferably three electrodes 102 and a sensing membrane (not shown)disposed over the electrodes 102 and/or the entire sensing region 100.The sensing region includes the electrodes 102 and the sensing membrane,which are configured to measure glucose in a manner such as describedabove with reference to the sensing region of FIGS. 2 and 4. In oneembodiment, the sensing membrane is reusable and can be held on thesensing region 100 by a clip, such as described with reference to FIG.2. In alternative embodiments, the sensing membrane is reusable can bedisposed onto the sensing region using depositing or bonding techniquesknown in the art of polymers.

In order to maintain a preferred wetness of the sensing region 100, andparticularly of the sensing membrane, the integrated receiver housing 92includes a sterile solution chamber (not shown) located at the end ofthe receiving chamber 104 that receives the stylus for storage, suchthat when the stylus is in its storage position (FIG. 5A), the sensingmembrane is maintained in the sterile solution. A sterile solution port106 is in communication with the sterile solution chamber and allows forrefilling of the sterile solution chamber using a sterile refillsolution 108.

Typically, when a biological sample 106 (FIG. 5E) is placed on asurface, such as the surface of the sensing membrane and/or sensingregion 100, there is a concern about contamination of the surface afteruse of the biological sample 106. Therefore, a single-use disposablebioprotective film 109 can be placed over the sensing region 100 toprovide protection from contamination. The disposable film 109 can beany film with that allows the passage of glucose, but blocks the passageof undesired species in the blood that could damage or contaminate thesensing membrane and/or cause inaccurate measurements (for example, athin film of very low molecular weight cutoff to prevent the transportof proteins, viruses, etc).

In some alternative embodiments, the bioprotective film 109 furthercomprises a sensing membrane formed as a part of the film (for example,laminated to the film), instead of (or in addition to) a sensingmembrane disposed on the sensing region. This alternative embodiment isparticularly advantageous in that it provides a disposable sensingmembrane that requires no cleaning step, for example.

Because the stylus 98 can be put into direct contact with the biologicalsample 106 (for example, on a finger or arm), no transfer mechanism isrequired, and therefore the sample size can be smaller thanconventionally required. Additionally, sensing region 100 does notrequire a separate cleaning step, because the disposable film 109 fullyprotects the sensing region 100 from contamination, and should bedisposed of after use.

The integrated receiver 92 housing further allows for storage anddispensing of the disposable films 109. A shuttle mechanism 110 isprovided that preferably feeds the films 109 into a spring-loadedstorage chamber (not shown) beneath the shuttle mechanism 110, or thelike. The shuttle mechanism 110 can be used to load the disposable films109, one at a time, into a dispensing chamber 111 for dispensing ontothe sensing region. In alternative embodiments, other storage anddispensing mechanisms can be configured as a part of the integratedreceiver housing 12 or separate therefrom.

In practice, the stylus 98 is held in its storage position within thereceiving chamber 104 where it is protected and maintained with apreferred wetness (FIG. 5A). A user then withdrawals the stylus 98 fromthe receiving chamber 104 (FIG. 5B) and loads a disposable film 109 bysliding the shuttle mechanism 110 toward the dispensing chamber 111.When the sensing region 100 of the stylus 98 presses on the disposablefilm 109 within the dispensing chamber, the film will be stretched overand/or otherwise stick to the moist sensing membrane on the surface ofthe sensing region 100 (FIG. 5D). At this point, the stylus 98 is readyfor a biological sample (for example, blood sample) 106. The stylus 98can be brought into contact with the finger or arm of the user todirectly receive the biological sample from the user without the needfor a transfer mechanism (FIG. 5E). After the test, the disposable filmis removed from the sensing region and the stylus 98 is replaced intothe receiving chamber 104 of the integrated receiver 92.

In this embodiment, the sensing region measures the glucoseconcentration of the biological sample in a manner such as describedwith reference to FIGS. 2 and 4, above. The integrated receiver'selectronics, including data processing and calibration, are described inmore detail below with reference to FIG. 8.

FIGS. 6A to 6J illustrate yet another embodiment of an integratedreceiver, including a single point glucose monitor, electronics, and adisposable filtering capillary tube. FIG. 6A is a perspective view ofthe integrated receiver in yet another embodiment, including a singlepoint glucose monitor and a disposable capillary tube for transferring abiological sample to a sensing region on the monitor. FIG. 6B is aperspective view of the integrated receiver of FIG. 6A, showing thedisposable capillary tube inserted into the single point glucose monitorto transfer the biological sample to a sensing region on the singlepoint glucose monitor. FIG. 6C is an expanded perspective view of aportion of the integrated receiver of FIG. 6A, showing the capillarytube inserted into the single point glucose monitor. FIG. 6D is aschematic cross-sectional view of a portion of the integrated receiverof FIG. 6A, illustrating the capillary tube in contact with a sensingmembrane such that glucose from the biological sample can be measured byelectrodes on the sensing region. FIG. 6E is a schematic cross-sectionalview of the capillary tube of FIG. 6A, illustrating an embodimentwherein a filter is located on one end. FIG. 6F is a schematiccross-sectional view of the capillary tube of FIG. 6A, illustrating anembodiment wherein a filter is disposed between two ends. FIG. 6G is aschematic cross-sectional view of the capillary tube of FIG. 6A,illustrating an embodiment wherein a vent extends from the capillarytube. FIG. 6H is a schematic illustration of one embodiment, wherein thecapillary tube 132 is round in shape with an inner capillary tube thatis also round in shape. FIG. 6I is a schematic illustration of oneembodiment, wherein the capillary tube 132 is rectangular in shape withan inner capillary tube 144 that is formed therein. FIG. 6J is aschematic illustration of one embodiment, wherein the capillary tube 132is rectangular in shape an inner capillary tube 144 has a roundedstructure.

In this embodiment, the integrated receiver provides a housing 112 thatintegrates a single point glucose monitor 114 and electronics (see FIG.8) useful to receive, process, and display data on a user interface 116.The single point glucose monitor 114 permits rapid and accuratemeasurement of the amount of a particular substance (for example,glucose) in a biological sample. Generally, the electronics that processsingle point glucose monitor data, receive and process continuousglucose sensor data, including calibration of the continuous sensor datausing the single point monitor data for example, and output data via theuser interface 116, are described below in more detail with reference toFIG. 8. Buttons 118 can be provided on this or any of the preferredintegrated receiver embodiments in order to facilitate user interactionwith the integrated receiver.

The single point glucose monitor 114 includes a sensor port 120configured to receive a biological fluid and measure its glucoseconcentration therefrom. As best illustrated in FIG. 6D, a sensingregion 122, which includes a sensing membrane 124 (such as described inmore detail elsewhere herein), is located within the sensor port 120.The sensing region includes electrodes 126, the top ends of which are incontact with an electrolyte phase (not shown), which is a free-flowingfluid phase disposed between the sensing membrane 124 and the electrodes126. The sensing region 122 measures glucose in the biological sample ina manner such as described in more detail above, with reference to thesensing regions of FIGS. 2, 4, and 5. In some embodiments, the sensorport 120 includes a cover (not shown) configured to cover the sensingmembrane 124 when the single glucose monitor is not in use in order tomaintain a preferred wetness of the sensing region 122, and particularlyof the sensing membrane.

Typically, when a biological sample is placed in on a surface (e.g., thesensing membrane 124), there is a concern about contamination of thesurface from the biological sample. Therefore, a single-use disposablecapillary tube 132 can be provided to transport and filter thebiological sample, for example from a blood sample of a finger or arm,to the sensing region 122. The disposable capillary tube 132 usescapillary action to draw the biological sample from a first end 134 to asecond end 136 of the capillary tube 132. A filter 140 is providedwithin the capillary tube 132, which is designed to allow the passage ofglucose, but filter or block the passage of undesired species in thebiological sample that could damage or contaminate the sensing membraneand/or cause inaccurate measurements (for example, the filter can beformed from a membrane of very low molecular weight cutoff to preventthe transport of proteins, viruses, etc). Because the filter 140protects the sensing region 122 from contamination, the sensing regiondoes not require a separate cleaning step, and the filter should bedisposed of after use.

Referring now to FIGS. 6E to 6G, various embodiments of the filterwithin the capillary tube are illustrated. Each capillary tube 132 has acapillary inlet 142 at a first end 134, an inner capillary tube 144, afilter 140, and an outlet 146 on the second end 136. The capillary tube132 enables the transport of blood or other aqueous solutions from thecapillary inlet 142 to the capillary outlet 146. The fluid transport isfacilitated by capillary action and preferably enabled by a hydrophilicsurface of the inner capillary tube 144. In some embodiments, someportions of the inner capillary tube 144 can be made hydrophobic tocontrol fluid flow. In some embodiments, the inner capillary tube 144has a volume between about 2 and 3 microliters; however a larger orsmaller volume is possible.

FIG. 6E is a schematic cross-sectional view of the capillary tube in oneembodiment, wherein a filter 140 is disposed at the second end 136within the inner capillary tube 144. This embodiment of the capillarytube is designed to filter the biological sample prior to its exit outof the capillary tube outlet 146.

FIG. 6F is a schematic cross-sectional view of the capillary tube inanother embodiment, wherein the filter 140 within the wall capillarytube 132 rather than within the inner capillary tube 144. In thisembodiment, the open inner capillary tube is designed to ensure accurateand repeatable fluid flow through the capillary tube by allowingdisplaced air to escape from the capillary tube outlet 146. As the fluidpasses through the inner capillary tube 144, at least a portion of thebodily fluid flows down through the filter 140 and exits the capillarytube 132 through a side exit 141. In some embodiments, the surface ofthe inner capillary tube 144 near the second end of the capillary can bealtered to be hydrophobic thereby preventing blood from escaping thesecond end.

FIG. 6G is a schematic cross-sectional view of the capillary tube in yetanother embodiment, wherein the capillary tube further comprises a vent148. This embodiment of the capillary tube is designed to ensureaccurate and repeatable fluid flow through the capillary tube, byallowing displaced air and other gases to escape from the vent 148,which is located on a side of the capillary tube at a position theallows air to escape prior to filtering of the biological fluid throughthe filter 140.

Referring now to FIGS. 6H to 6J, various embodiments of the capillarytube structure are illustrated. The schematic views are intended to beexemplary and do not represent scale or proportion of the capillarytubes.

FIG. 6H is a schematic illustration of one embodiment, wherein thecapillary tube 132 is round in shape with an inner capillary tube thatis also round in shape. This is an embodiment similar to that shown inFIG. 6A to 6D, and optionally includes a tab, wings, or other structureto aid in handling and/or mechanical alignment of the tube 132.

FIG. 6I is a schematic illustration of one embodiment, wherein thecapillary tube 132 is rectangular in shape with an inner capillary tube144 that is formed therein. In one embodiment, the inner capillary tube144 can be formed by methods, for example as known in the art ofmanufacturing test strips used for self-monitoring blood glucose meters.

FIG. 6J is a schematic illustration of one embodiment; wherein thecapillary tube 132 is rectangular in shape an inner capillary tube 144has a rounded structure. Shape, dimensions, proportions, or the like donot limit the capillary tube of the preferred embodiments, provided thatthe capillary tube is capable of performing capillary action.

The capillary tubes 132 can be manufactured using materials such asplastic, glass, silicon, or the like. In one embodiment, the preferredmanufacturing material is plastic because of its low cost and theavailability of numerous manufacturing processes. The inner capillarytube 144 can be molded or embossed to form the capillary structure. Insome alternative embodiments, such as shown FIG. 6I, the inner capillarytube 144 can be formed by multi-layers including a top-capping layerthat forms the capillary structure. Adhesive, ultrasonic bonding,solvents or other methods can be used to bond the layers. Holding tabsare not employed in certain embodiments of the capillary tube dependingon their structure, for example the capillary tubes shown in FIGS. 6H to6J.

In some embodiments, it can be advantageous to place a means ofdetecting a proper fill of the capillary. This can be accomplished forexample by electrical means, optical means, or the like. In someembodiments (not shown), the integrated receiver housing 112 can bedesigned with a means for storing and dispensing capillary tubes 132. Inalternative embodiments, other storage and/or dispensing means can beconfigured separate from the integrated receiver housing 112.

In practice, a user obtains a biological sample from a source, such as afinger or forearm (in some alternative embodiments, the single pointglucose monitor can by designed to measure biological fluids other thanblood, such as urine, sweat, or the like). The user then grasps adisposable capillary tube 132 (e.g., tab or outer surface) and contactsthe source with the capillary inlet 142. Because of the design of theinner capillary tube 144, capillary action causes the biological sampleto be drawn towards the capillary outlet 146. The biological sample isfiltered as it passes through the filter 140, which is permeable toglucose but impermeable to large molecules and species in the blood thatcan clog, damage, or contaminate the sensing membrane 124, and/or causeinaccurate measurements. Therefore, the biological sample permeates thefilter 140 and into the sensing membrane 124 (for example, fluid contactbetween the capillary tube and sensing membrane enables the transfer ofthe filtered biological sample), where it enyzmatically reacts with thecatalyst (e.g., glucose oxidase) and produces hydrogen peroxide.Hydrogen peroxide is detected by the electrochemical sensor, wherein theelectrical signal is converted into glucose value, such as described inmore detail elsewhere herein.

The sensing membrane 124 is a reusable component of the single pointglucose monitor, which advantageously provides a low cost associatedwith each glucose measurement as compared to conventional glucosemeasuring test strips. Additionally, the disposable capillary tube 132simplifies the cleanup of the device, as compared to conventional singlepoint glucose monitors that utilize similar enzyme membrane technology.Furthermore, because the blood remains within the capillary tube 144,which can be disposed of without contaminating the integrated receiverhousing 112 or the sensing membrane 124, the risk of human contact withblood is reduced.

FIGS. 7A and 7B are perspective views of yet another embodiment of anintegrated receiver, wherein the single point glucose monitor isdetachably connected to the receiver housing to provide a modularconfiguration. FIG. 7A is a perspective view of the integrated receiverin this embodiment, wherein the single point glucose monitor isdetachably connected to the receiver to form a modular configuration,shown in its connected state. FIG. 7B is a perspective view of theintegrated receiver of FIG. 7A, shown in its detached state.

In this embodiment, the integrated receiver 150 provides a receiverhousing 152 and a single point glucose monitor 154, which are detachablyconnectable to each other. The receiver housing 152 includes electronics(hardware and software) useful to receive, process, and display datafrom the continuous glucose sensor and/or the single point glucosesensor on a user interface 156, such as described in more detail withreference to FIG. 8. In some embodiments, some part of the electronics(for example, the electronics specific to the single point glucosemonitor 154) can be housed within the single point glucose monitor 154.The single point glucose monitor 154 can be configured as described withreference to FIG. 6, for example, to permit rapid and accuratemeasurements of the amount of a particular substance (for example,glucose) in a biological sample. In alternative embodiments, the singlepoint glucose monitor of this modular embodiment can be configured asdescribed with reference to any of the single point glucose monitors ofthe preferred embodiments. In yet alternative embodiments, the singlepoint glucose monitor can be configured using other known glucose meterconfigurations.

In general, this embodiment provides for a modular configuration betweena receiver housing 152 and a single point glucose monitor 154, whereinthe single point glucose monitor can be detached when a user prefers tocarry a smaller, simpler, or lighter device (for example, duringexercise). However, when a user is ready to perform a single pointglucose test, the glucose monitor 154 can be easily attached to thereceiver 152 to form an integrated receiver 150 with its numerousassociated advantages. In one embodiment, electrical contacts (notshown) on the receiver housing 152 and the single point glucose monitor154 allow an electrical connection to be established in its attachedposition. In another embodiment, a wireless connection between thereceiver housing 152 and the single point glucose monitor 154 can beprovided, wherein the integration is advantageous for its convenientone-piece system (for example, fewer loose parts), its similarmeasurement technologies (for example, enzyme membrane-basedelectrochemical measurement), and its added versatility to function evenwhen the modular device is detached.

While not required, it is preferred in this embodiment that the singlepoint glucose monitor 154 be dependent upon the integrated receiver 152for at least a portion of its operation. For example, at least some ofthe electronics and/or user interface for the single point glucosemonitor 154 are located within the receiver 152. Numerous advantagesassociated with the integrated receiver 150, such as ensuring accuratetime stamping of the single point glucose test at the receiver and otheradvantages described herein, can be provided by an integrated continuousglucose receiver and single point glucose monitor, such as describedherein.

Additionally, the integrated receiver housing configurations of thepreferred embodiments are advantageous in that they can be calibrated bythe user and can be designed with a measurement technique consistentwith that of the continuous glucose sensor. These and other advantagescan be seen in alternative embodiments of the device of the preferredembodiments, which are described in more detail elsewhere herein.

In one alternative embodiment, the single point glucose monitorcomprises an integrated lancing and measurement device such as describedin U.S. Pat. No. 6,607,658 to Heller et al. In another alternativeembodiment, the single point glucose monitor comprises a near infrareddevice such as described in U.S. Pat. No. 5,068,536 to Rosenthal et al.In another alternative embodiment, the single point glucose monitorcomprises an integrated lancer, blood-monitoring device, and medicationdelivery pen, such as described in U.S. Pat. No. 6,192,891 to Gravel etal. In another alternative embodiment, the single point glucose monitorcomprises a reflectance reading apparatus such as described in U.S. Pat.No. 5,426,032 to Phillips et al. In another alternative embodiment, thesingle point glucose monitor comprises a spectroscopic transflectancedevice such as described in U.S. Pat. No. 6,309,884 to Cooper et al.Other integrations that can be combined with the integrated receiver aredescribed in co-pending U.S. patent application Ser. No. 10/789,359,filed Feb. 26, 2004. All of the above patents and patent applicationsare incorporated in their entirety herein by reference.

FIG. 8 is a block diagram that illustrates integrated receiverelectronics in one embodiment. The described electronics are applicableto the preferred embodiments, including the integrated receiver 12 ofFIGS. 1, 4A, and 4B, the integrated receiver 92 of FIGS. 5A to 5E, theintegrated receiver 112 of FIGS. 6A to 6D, and the integrated receiver150 of FIGS. 7A and 7B.

A quartz crystal 160 is operably connected to an RF transceiver 162,which together function to receive and synchronize data streams 164 viaan antenna 166 (for example, transmission 46 from the RF transceiver 44shown in FIG. 3). Once received, a microprocessor 168 processes thesignals, such as described below.

The microprocessor 168 is the central control unit that provides theprocessing, such as storing data, analyzing continuous glucose sensordata stream, analyzing single point glucose values, accuracy checking,checking clinical acceptability, calibrating sensor data, downloadingdata, and controlling the user interface by providing prompts, messages,warnings and alarms, or the like. The EEPROM 170 is operably connectedto the microprocessor 168 and provides semi-permanent storage of data,storing data such as receiver ID and programming to process data streams(for example, programming for performing calibration and otheralgorithms described elsewhere herein). SRAM 172 is used for thesystem's cache memory and is helpful in data processing. For example,the SRAM stores information from the continuous glucose sensor and thesingle point glucose monitor for later recall by the user or a doctor; auser or doctor can transcribe the stored information at a later time todetermine compliance with the medical regimen or a comparison of glucoseconcentration to medication administration (for example, this can beaccomplished by downloading the information through the pc corn port174). In addition, the SRAM 172 can also store updated programinstructions and/or patient specific information. FIGS. 9 and 10describe more detail about programming that is preferably processed bythe microprocessor 168. In some alternative embodiments, memory storagecomponents comparable to EEPROM and SRAM can be used instead of or inaddition to the preferred hardware, such as dynamic RAM, non-static RAM,rewritable ROMs, flash memory, or the like.

A battery 176 is operably connected to the microprocessor 168 andprovides power for the receiver. In one embodiment, the battery is astandard AAA alkaline battery, however any appropriately sized andpowered battery can be used. In some embodiments, a plurality ofbatteries can be used to power the system. In some embodiments, a powerport (not shown) is provided permit recharging of rechargeablebatteries. A quartz crystal 178 is operably connected to themicroprocessor 168 and maintains system time for the computer system asa whole.

A PC communication (com) port 174 can be provided to enablecommunication with systems, for example, a serial communications port,allows for communicating with another computer system (for example, PC,PDA, server, or the like). In one exemplary embodiment, the receiver isable to download historical data to a physician's PC for retrospectiveanalysis by the physician. The PC communication port 174 can also beused to interface with other medical devices, for example pacemakers,implanted analyte sensor patches, infusion devices, telemetry devices,or the like.

Electronics associated with the single point glucose monitor 180 areoperably connected to the microprocessor 168 and include a potentiostat181 in one embodiment that measures a current flow produced at theworking electrode when a biological sample is placed on the sensingmembrane, such as described with reference to FIGS. 4 to 7, for example.The current is then converted into an analog signal by a current tovoltage converter, which can be inverted, level-shifted, and sent to theA/D converter 182. The microprocessor can set the analog gain via itscontrol port (not shown). The A/D converter is preferably activated atone-second intervals. The microprocessor looks at the converter outputwith any number of pattern recognition algorithms known to those skilledin the art until a glucose peak is identified. A timer is thenpreferably activated for about 30 seconds at the end of which time thedifference between the first and last electrode current values iscalculated. This difference is then divided by the value stored in thememory during instrument calibration and is then multiplied by thecalibration glucose concentration. The glucose value in milligram perdeciliter, millimoles per liter, or the like, is then stored in themicroprocessor, displayed on the user interface, used to calibrate ofthe glucose sensor data stream, downloaded, etc.

A user interface 184 comprises a keyboard 186, speaker 188, vibrator190, backlight 192, liquid crystal display (LCD) 194, and one or morebuttons 196. The components that comprise the user interface 184 providecontrols to interact with the user. The keyboard 186 can allow, forexample, input of user information about an individual, such asmealtime, exercise, insulin administration, and reference glucosevalues. The speaker 188 can provide, for example, audible signals oralerts for conditions such as present and/or predicted hyper- andhypoglycemic conditions. The vibrator 190 can provide, for example,tactile signals or alerts for reasons such as described with referenceto the speaker, above. The backlight 192 can be provided, for example,to aid the user in reading the LCD in low light conditions. The LCD 194can be provided, for example, to provide the user with visual dataoutput. In some embodiments, the LCD is a touch-activated screen. Thebuttons 196 can provide for toggle, menu selection, option selection,mode selection, and reset, for example. In some alternative embodiments,a microphone can be provided to allow for voice-activated control.

The user interface 184, which is operably connected to themicroprocessor 168 serves to provide data input and output for both thecontinuous glucose sensor (for example, FIGS. 2 and 3) and for theintegrated receiver including the single point glucose monitor (forexample, FIGS. 4 to 7).

In some embodiments, prompts or messages can be displayed on the userinterface to guide the user through the initial calibration and samplemeasurement procedures for the single point glucose monitor.Additionally, prompts can be displayed to inform the user aboutnecessary maintenance procedures, such as “Replace Sensing Membrane” or“Replace Battery.” Even more, the glucose concentration value measuredfrom the single point glucose monitor can be individually displayed.

In some embodiments, prompts or messages can be displayed on the userinterface to convey information to the user, such as malfunction,outlier values, missed data transmissions, or the like, for thecontinuous glucose sensor. Additionally, prompts can be displayed toguide the user through calibration of the continuous glucose sensor.Even more, calibrated sensor glucose data, which is described in moredetail with reference to FIGS. 9 and 10, can be displayed in numericalor graphical representations, or the like.

Reference is now made to FIG. 9, which is a flow chart that illustratesthe process of initial calibration and data output of the glucose sensor10 in one embodiment. Calibration of the glucose sensor 10 generallyincludes data processing that converts a sensor data stream intoestimated glucose values that are meaningful to a user. Accordingly, areference glucose value can be used to calibrate the data stream fromthe glucose sensor 10. The calibration can be performed on a real-timebasis and/or backwards recalibrated (for example, retrospectively).

At block 200, a sensor data receiving module, also referred to as thesensor data module, receives sensor data (for example, a data stream),including one or more time-spaced sensor data points, hereinafterreferred to as “sensor data” or “sensor glucose data.” The integratedreceiver receives the sensor data from a continuous glucose sensor,which can be in wired or wireless communication with the integratedreceiver. Some or all of the sensor data point(s) can be smoothed orreplaced by estimated signal values such as described with reference toco-pending U.S. patent application entitled, “SYSTEMS AND METHODS FORREPLACING SIGNAL ARTIFACTS IN A GLUCOSE SENSOR DATA STREAM,” filed Aug.22, 2003. During the initialization of the sensor, prior to initialcalibration, the integrated receiver (for example, FIGS. 4 to 7)receives and stores the sensor data, however it does not necessarilydisplay any data to the user until initial calibration and optionallystabilization of the sensor 10 has been determined.

At block 202 a single point glucose module, also referred to as thereference input module, receives glucose data from the integrated singlepoint glucose monitor, including one or more reference glucose datapoints, hereinafter referred as “reference data” or “reference glucosedata.” Namely, the single point glucose monitor, such as described inmore detail with reference to FIGS. 4 to 7, which is integral with thereceiver, provides a reference glucose concentration value, such asdescribed above with respect to the single point glucose monitors of thepreferred embodiments. The reference glucose concentration value fromthe single point glucose monitor is calibrated such as described abovein more detail with reference to FIG. 8.

In some embodiments, the microprocessor 168 monitors the continuousglucose sensor data stream to determine a preferable time for capturingglucose concentration values using the single point glucose monitorelectronics 180 for calibration of the continuous sensor data stream.For example, when sensor glucose data (for example, observed from thedata stream) changes too rapidly, a single point glucose monitor readingmay not be sufficiently reliable for calibration during unstable glucosechanges in the host; in contrast, when sensor glucose data arerelatively stable (for example, relatively low rate of change), a singlepoint glucose monitor reading can be taken for a reliable calibration.In some additional embodiments, the microprocessor can prompt the uservia the user interface to obtain a single point glucose value forcalibration at predetermined intervals. In some additional embodiments,the user interface can prompt the user to obtain a single point glucosemonitor value for calibration based upon certain events, such as meals,exercise, large excursions in glucose levels, faulty or interrupted datareadings, or the like. In some embodiments, certain acceptabilityparameters can be set for reference values received from the singlepoint glucose monitor. For example, in one embodiment, the receiver onlyaccepts reference glucose data between about 40 and about 400 mg/dL.

At block 204, a data matching module, matches reference data (forexample, one or more reference glucose data points) with substantiallytime corresponding sensor data (for example, one or more sensor datapoints) to provide one or more matched data pairs. In one embodiment,one reference data point is matched to one time corresponding sensordata point to form a matched data pair. In another embodiment, aplurality of reference data points are averaged (for example, equally ornon-equally weighted average, mean-value, median, or the like) andmatched to one time corresponding sensor data point to form a matcheddata pair. In another embodiment, one reference data point is matched toa plurality of time corresponding sensor data points averaged to form amatched data pair. In yet another embodiment, a plurality of referencedata points are averaged and matched to a plurality of timecorresponding sensor data points averaged to form a matched data pair.

In one embodiment, time corresponding sensor data comprises one or moresensor data points that occur, for example, 15±5 min after the referenceglucose data timestamp (for example, the time that the reference glucosedata is obtained). In this embodiment, the 15 minute time delay has beenchosen to account for an approximately 10 minute delay introduced by thefilter used in data smoothing and an approximately 5 minutephysiological time-lag (for example, the time necessary for the glucoseto diffusion through a membrane(s) of a glucose sensor). In alternativeembodiments, the time corresponding sensor value can be more or lessthan in the above-described embodiment, for example ±60 minutes.Variability in time correspondence of sensor and reference data can beattributed to, for example, a longer or shorter time delay introducedduring signal estimation, or if the configuration of the glucose sensor10 incurs a greater or lesser physiological time lag.

One advantage of integrated receiver of the preferred embodiments can beseen in the time stamp of the reference glucose data. Namely, typicalimplementations of the continuous glucose sensor 10, wherein the singlepoint glucose monitor is not integral with the receiver, the referenceglucose data can be obtained at a time that is different from the timethat the data is input into the receiver 30. Thus, the user may notaccurately input the “time stamp” of the reference glucose (for example,the time at which the reference glucose value was actually obtained) atthe time of reference data input into the receiver. Therefore, theaccuracy of the calibration is subject to human error (for example, dueto inconsistencies in entering the actual time of the single pointglucose test). In contrast, the preferred embodiments of the integratedreceiver advantageously do no suffer from this potential inaccuracy inthat the time stamp is automatically and accurately obtained at the timeof single point glucose test. Additionally, the process of obtainingreference data is simplified and made convenient using the integratedreceiver because of fewer loose parts (for example, cables, test strips,or the like) and less required data entry (for example, time oftesting).

In some embodiments, tests are used to evaluate the best-matched pairusing a reference data point against individual sensor values over apredetermined time period (for example, about 30 minutes). In one suchembodiment, the reference data point is matched with sensor data pointsat 5-minute intervals and each matched pair is evaluated. The matchedpair with the best correlation can be selected as the matched pair fordata processing. In some alternative embodiments, matching a referencedata point with an average of a plurality of sensor data points over apredetermined time period can be used to form a matched pair.

At block 206, a calibration set module, forms an initial calibration setfrom a set of one or more matched data pairs, which are used todetermine the relationship between the reference glucose data and thesensor glucose data, such as described in more detail with reference toblock 208, below.

The matched data pairs, which make up the initial calibration set, canbe selected according to predetermined criteria. In some embodiments,the number (n) of data pair(s) selected for the initial calibration setis one. In other embodiments, n data pairs are selected for the initialcalibration set wherein n is a function of the frequency of the receivedreference glucose data points. In one exemplary embodiment, six datapairs make up the initial calibration set. In another embodiment, thecalibration set includes only one data pair.

In some embodiments, the data pairs are selected only within a certainglucose value threshold, for example wherein the reference glucose valueis between about 40 and about 400 mg/dL. In some embodiments, the datapairs that form the initial calibration set are selected according totheir time stamp.

At block 208, a conversion function module creates a conversion functionusing the calibration set. The conversion function substantially definesthe relationship between the reference glucose data and the sensorglucose data. A variety of known methods can be used with the preferredembodiments to create the conversion function from the calibration set.In one embodiment, wherein a plurality of matched data points form theinitial calibration set, a linear least squares regression is performedon the initial calibration set such as described in more detail withreference to FIG. 10.

At block 210, a sensor data transformation module uses the conversionfunction to transform sensor data into substantially real-time glucosevalue estimates, also referred to as calibrated data, as sensor data iscontinuously (or intermittently) received from the sensor. In otherwords, the offset value at any given point in time can be subtractedfrom the raw value (for example, in counts) and divided by the slope toobtain the estimated glucose value:

${{mg}\text{/}{dL}} = \frac{\left( {{rawvalue} - {offset}} \right)}{slope}$

In some alternative embodiments, the sensor and/or reference glucosedata are stored in a database for retrospective analysis.

At block 212, an output module provides output to the user via the userinterface. The output is representative of the estimated glucose value,which is determined by converting the sensor data into a meaningfulglucose value such as described in more detail with reference to block210, above. User output can be in the form of a numeric estimatedglucose value, an indication of directional trend of glucoseconcentration, and/or a graphical representation of the estimatedglucose data over a period of time, for example. Other representationsof the estimated glucose values are also possible, for example audio andtactile.

In one embodiment, the estimated glucose value is represented by anumeric value. In other exemplary embodiments, the user interfacegraphically represents the estimated glucose data trend over apredetermined time period (for example, one, three, and nine hours,respectively). In alternative embodiments, other time periods can berepresented. In alternative embodiments, pictures, animation, charts,graphs, and numeric data can be selectively displayed.

Accordingly, after initial calibration of the sensor, real-timecontinuous glucose information can be displayed on the user interface sothat the user can regularly and proactively care for his/her diabeticcondition within the bounds set by his/her physician. Both thecalibrated reference glucose data from the single point glucose monitorand the sensor glucose data from the continuous glucose sensor can bedisplayed to the user. In an embodiment wherein the continuous glucosesensor functions as an adjunctive device to the single point glucosemonitor, the user interface can display numeric reference glucose data,while showing the sensor glucose data only in a graphical representationso that the user can see the historical and present sensor trendinformation as well as the most recent reference glucose data value. Inan embodiment wherein the continuous glucose sensor functions as anon-adjunctive device to the single point glucose monitor, the userinterface can display the reference glucose data and/or the sensorglucose data. The user can toggle through menus and screens using thebuttons in order to view alternate data and/or screen formats, forexample.

In alternative embodiments, the conversion function is used to predictglucose values at future points in time. These predicted values can beused to alert the user of upcoming hypoglycemic or hyperglycemic events.Additionally, predicted values can be used to compensate for the timelag (for example, 15 minute time lag such as described elsewhereherein), so that an estimated glucose value displayed to the userrepresents the instant time, rather than a time delayed estimated value.

In some embodiments, the substantially real-time estimated glucosevalue, a predicted future estimated glucose value, a rate of change,and/or a directional trend of the glucose concentration is used tocontrol the administration of a constituent to the user, including anappropriate amount and time, in order to control an aspect of the user'sbiological system. One such example is a closed loop glucose sensor andinsulin pump, wherein the glucose data (for example, estimated glucosevalue, rate of change, and/or directional trend) from the glucose sensoris used to determine the amount of insulin, and time of administration,that can be given to a diabetic user to evade hyper- and hypoglycemicconditions.

FIG. 10 is a graph that illustrates one embodiment of a regressionperformed on a calibration set to create a conversion function such asdescribed with reference to FIG. 9, block 208, above. In thisembodiment, a linear least squares regression is performed on theinitial calibration set. The x-axis represents reference glucose data;the y-axis represents sensor data. The graph pictorially illustratesregression of matched pairs 214 in the calibration set. The regressioncalculates a slope 216 and an offset 218, for example, using thewell-known slope-intercept equation (y=m×+b), which defines theconversion function.

In alternative embodiments, other algorithms could be used to determinethe conversion function, for example forms of linear and non-linearregression, for example fuzzy logic, neural networks, piece-wise linearregression, polynomial fit, genetic algorithms, and other patternrecognition and signal estimation techniques.

In yet other alternative embodiments, the conversion function cancomprise two or more different optimal conversions because an optimalconversion at any time is dependent on one or more parameters, such astime of day, calories consumed, exercise, or glucose concentration aboveor below a set threshold, for example. In one such exemplary embodiment,the conversion function is adapted for the estimated glucoseconcentration (for example, high vs. low). For example in an implantableglucose sensor it has been observed that the cells surrounding theimplant will consume at least a small amount of glucose as it diffusestoward the glucose sensor. Assuming the cells consume substantially thesame amount of glucose whether the glucose concentration is low or high,this phenomenon will have a greater effect on the concentration ofglucose during low blood sugar episodes than the effect on theconcentration of glucose during relatively higher blood sugar episodes.Accordingly, the conversion function can be adapted to compensate forthe sensitivity differences in blood sugar level. In one implementation,the conversion function comprises two different regression lines,wherein a first regression line is applied when the estimated glucoseconcentration is at or below a certain threshold (for example, 150mg/dL) and a second regression line is applied when the estimatedglucose concentration is at or above a certain threshold (for example,150 mg/dL). In one alternative implementation, a predetermined pivot ofthe regression line that forms the conversion function can be appliedwhen the estimated blood is above or below a set threshold (for example,150 mg/dL), wherein the pivot and threshold are determined from aretrospective analysis of the performance of a conversion function andits performance at a range of glucose concentrations. In anotherimplementation, the regression line that forms the conversion functionis pivoted about a point in order to comply with clinical acceptabilitystandards (for example, Clarke Error Grid, Consensus Grid, mean absoluterelative difference, or other clinical cost function) and/orphysiological parameters. Although only a few example implementationsare described, other embodiments include numerous implementationswherein the conversion function is adaptively applied based on one ormore parameters that can affect the sensitivity of the sensor data overtime.

The preferred embodiments described a continuous glucose sensor andintegrated receiver with single point glucose calibration that is morecost effective than conventional reference glucose monitors (forexample, more cost effective than test strips). Additionally, theconsistency between the similar measurement technologies used both forthe continuous sensor and the single point glucose monitor increases theconsistency and decreases the cause for error between the twomeasurements devices, yielding a more reliable, accurate device.

In some alternative embodiments similarly advantageous results can beprovided that by combined continuous glucose sensor and integratedreceiver configurations wherein the measurement technologies areconsistent between the continuous glucose sensor and single pointglucose monitor. For example, an optical, non-invasive, “continuous orquasi-continuous” glucose measurement device such as described by U.S.Pat. No. 6,049,727, which is incorporated by reference herein in itsentirety, can be implanted in the body. An integrated receiver can beprovided that processes sensor data and includes an optical non-invasivesingle point glucose monitor such as described with reference to U.S.Pat. No. 6,309,884, which is incorporated by reference herein in itsentirety. Accordingly, when optical-based technology is used both forthe continuous sensor and the single point glucose monitor, increasedconsistency and decreased cause for error between the two measurementsdevices exist, yielding a more reliable, accurate device. Otherembodiments can be provided that utilize consistent measurementtechnologies between a continuous analyte sensor and a single pointanalyte monitor useful for calibration such as described herein and arewithin the spirit of the preferred embodiments.

Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in co-pending U.S.patent application Ser. No. 10/885,476 filed Jul. 6, 2004, and entitled“SYSTEMS AND METHODS FOR MANUFACTURE OF AN ANALYTE-MEASURING DEVICEINCLUDING A MEMBRANE SYSTEM”; U.S. patent application Ser. No.10/842,716, filed May 10, 2004, and entitled, “MEMBRANE SYSTEMSINCORPORATING BIOACTIVE AGENTS”; co-pending U.S. patent application Ser.No. 10/838,912 filed May 3, 2004, and entitled, “IMPLANTABLE ANALYTESENSOR”; U.S. patent application Ser. No. 10/789,359 filed Feb. 26,2004, and entitled, “INTEGRATED DELIVERY DEVICE FOR A CONTINUOUS GLUCOSESENSOR”; U.S. application Ser. No. 10/685,636 filed Oct. 28, 2003, andentitled, “SILICONE COMPOSITION FOR MEMBRANE SYSTEM”; U.S. applicationSer. No. 10/648,849 filed Aug. 22, 2003, and entitled, “SYSTEMS ANDMETHODS FOR REPLACING SIGNAL ARTIFACTS IN A GLUCOSE SENSOR DATA STREAM”;U.S. application Ser. No. 10/646,333 filed Aug. 22, 2003, entitled,“OPTIMIZED SENSOR GEOMETRY FOR AN IMPLANTABLE GLUCOSE SENSOR”; U.S.application Ser. No. 10/647,065 filed Aug. 22, 2003, entitled, “POROUSMEMBRANES FOR USE WITH IMPLANTABLE DEVICES”; U.S. application Ser. No.10/633,367 filed Aug. 1, 2003, entitled, “SYSTEM AND METHODS FORPROCESSING ANALYTE SENSOR DATE”; U.S. Pat. No. 6,702,857 entitled“MEMBRANE FOR USE WITH IMPLANTABLE DEVICES”; U.S. application Ser. No.09/916,711 filed Jul. 27, 2001, and entitled “SENSOR HEAD FOR USE WITHIMPLANTABLE DEVICE”; U.S. application Ser. No. 09/447,227 filed Nov. 22,1999, and entitled “DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS”;U.S. application Ser. No. 10/153,356 filed May 22, 2002, and entitled“TECHNIQUES TO IMPROVE POLYURETHANE MEMBRANES FOR IMPLANTABLE GLUCOSESENSORS”; U.S. application Ser. No. 09/489,588 filed Jan. 21, 2000, andentitled “DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS”; U.S.application Ser. No. 09/636,369 filed Aug. 11, 2000, and entitled“SYSTEMS AND METHODS FOR REMOTE MONITORING AND MODULATION OF MEDICALDEVICES”; and U.S. application Ser. No. 09/916,858 filed Jul. 27, 2001,and entitled “DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS,” as wellas issued patents including U.S. Pat. No. 6,001,067 issued Dec. 14,1999, and entitled “DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS”;U.S. Pat. No. 4,994,167 issued Feb. 19, 1991, and entitled “BIOLOGICALFLUID MEASURING DEVICE”; and U.S. Pat. No. 4,757,022 filed Jul. 12,1988, and entitled “BIOLOGICAL FLUID MEASURING DEVICE”; U.S. Appl. No.60/489,615 filed Jul. 23, 2003, and entitled “ROLLED ELECTRODE ARRAY ANDITS METHOD FOR MANUFACTURE”; U.S. Appl. No. 60/490,010 filed Jul. 25,2003, and entitled “INCREASING BIAS FOR OXYGEN PRODUCTION IN ANELECTRODE ASSEMBLY”; U.S. Appl. No. 60/490,009 filed Jul. 25, 2003, andentitled “OXYGEN ENHANCING ENZYME MEMBRANE FOR ELECTROCHEMICAL SENSORS”;U.S. application Ser. No. 10/896,312 filed Jul. 21, 2004, and entitled“OXYGEN-GENERATING ELECTRODE FOR USE IN ELECTROCHEMICAL SENSORS”; U.S.application Ser. No. 10/896,637 filed Jul. 21, 2004, and entitled“ROLLED ELECTRODE ARRAY AND ITS METHOD FOR MANUFACTURE”; U.S.application Ser. No. 10/896,772 filed Jul. 21, 2004, and entitled“INCREASING BIAS FOR OXYGEN PRODUCTION IN AN ELECTRODE ASSEMBLY”; U.S.application Ser. No. 10/896,639 filed Jul. 21, 2004, and entitled“OXYGEN ENHANCING ENZYME MEMBRANE FOR ELECTROCHEMICAL SENSORS”; U.S.application Ser. No. 10/897,377 filed Jul. 21, 2004, and entitled“ELECTROCHEMICAL SENSORS INCLUDING ELECTRODE SYSTEMS WITH INCREASEDOXYGEN GENERATION”. The foregoing patent applications and patents areincorporated herein by reference in their entireties.

All references cited herein are incorporated herein by reference intheir entireties. To the extent publications and patents or patentapplications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

The term “comprising” as used herein is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that can varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

The above description discloses several methods and materials of thepresent invention. This invention is susceptible to modifications in themethods and materials, as well as alterations in the fabrication methodsand equipment. Such modifications will become apparent to those skilledin the art from a consideration of this disclosure or practice of theinvention disclosed herein. Consequently, it is not intended that thisinvention be limited to the specific embodiments disclosed herein, butthat it cover all modifications and alternatives coming within the truescope and spirit of the invention as embodied in the attached claims.

1. A system comprising: a continuous sensor configured for at leastpartial insertion into a host, wherein the continuous sensor generatescontinuous sensor data associated with an analyte concentration in thehost; a single point monitor external to the host, wherein the singlepoint monitor generates at least one single point value associated withan analyte concentration of a biological sample received from the host;and a processing unit configured to calibrate the continuous sensor datausing the single point value from the single point monitor, wherein theprocessing unit is in data communication with the continuous sensor andconfigured to receive and process the continuous sensor data from thecontinuous sensor, and wherein the single point monitor is physicallyconnected to the processing unit.
 2. The system of claim 1, wherein eachof the continuous sensor and the single point monitor comprise a sensingmembrane comprising an enzyme domain, and wherein the enzyme domain ofthe sensing membrane of the continuous sensor and the enzyme domain ofthe sensing membrane of the single point monitor are substantially thesame.
 3. The system of claim 1, wherein the single point monitor isconfigured to receive a single use test strip.
 4. The system of claim 1,wherein the processing unit further comprises programming to controladministration of a constituent to the host.
 5. The system of claim 4,wherein the programming to control administration of a constituent tothe host is configured to determine at least one of an amount of insulinand a time of insulin administration.
 6. The system of claim 1, whereinthe processing unit further comprises programming to calculate a rate ofchange of the continuous sensor data and/or directional trend of thecontinuous sensor data.
 7. The system of claim 6, wherein the processingunit further comprises programming to control administration of aconstituent to the host based at least in part on a rate of change ofthe continuous sensor data and/or a directional trend of the continuoussensor data.
 8. The system of claim 1, wherein the processing unitfurther comprises programming to control administration of a constituentto the host based at least in part on the at least one single pointvalue.
 9. The system of claim 1, wherein the processing unit isconfigured to monitor the continuous sensor data to adaptively determinea time for requesting a biological sample.
 10. The system of claim 1,further comprising a user interface associated with the processing unitand the single point monitor, wherein the processing unit is configuredto prompt the user, via the user interface, to provide a biologicalsample to the single point monitor at predetermined intervals.
 11. Thesystem of claim 1, further comprising a user interface associated withthe processing unit and the single point monitor, wherein the processingunit is configured to prompt the user to provide a biological sample tothe single point monitor based upon one or more events.
 12. The systemof claim 11, wherein the one or more events comprise one or more eventsselected from the group consisting of meals, exercise, large excursionsin analyte levels, and faulty or interrupted data readings.
 13. Thesystem of claim 1, wherein processing unit is configured to compare thesingle point value with one or more acceptability parameters.
 14. Thesystem of claim 1, further comprising a user interface associated withthe processing unit and the single point monitor, wherein the userinterface is configured to display the single point value from thesingle point monitor and the continuous sensor data from the continuoussensor on the user interface.
 15. The system of claim 1, furthercomprising a user interface associated with the processing unit and thesingle point monitor, wherein the user interface is configured tosimultaneously display the single point value and a graphicalrepresentation of the continuous sensor data.
 16. The system of claim 1,further comprising a user interface associated with the processing unitand the single point monitor, wherein the user interface is configuredto selectively display the single point value and the continuous sensordata responsive to user interaction.
 17. The system of claim 1, furthercomprising a drug delivery device, and wherein the processing unit is indata communication with the drug delivery device.